Synthesis, Stability Studies, Anti-inflammatory Activity and Ulcerogenicity of Morpholinoalkyl Ester Prodrugs of Niflumic Acid

Abstract

In search for potential prodrugs for anti-inflammatory drug candidates in the niflumate series, novel morpholinoalkyl ester prodrugs of niflumic acid (CAS 4394-00-7) 5a-b were prepared by esterification of appropriate morpholinylalkyl alcohols 3a-b with niflumic acid 4 in the presence of dicyclohexyl carbodiimide (DCC) and catalyst dimethylamino pyridine (DMAP) at 0-5 degrees C. The structures were confirmed by elemental and spectral data (UV, IR, 1H-NMR, 13C-NMR, and EI-MS). The ester prodrugs 5a-b showed better solubility than the parent drug niflumic acid 4 in simulated gastric fluid (SGF) and phosphate buffer (pH 7.4). The in vitro hydrolysis studies were conducted at pH 1.3 (SGF), phosphate buffer (pH 7.4) and in human plasma diluted with phosphate buffer (pH 7.4) at 37+/-0.5 degrees C using HPLC with UV detection. The ester prodrugs 5a-b were quantitatively hydrolyzed to the parent drug niflumic acid 4 by enzymatic and/or chemical means. It is observed that an increase in the carbon chain length rendered the prodrugs 5a-b more stable in phosphate buffer (pH 7.4) than in pH 1.3 (SGF), but they were rapidly hydrolyzed in human plasma at 37+/-0.5 degrees C. They exhibited longer hydrolytic half-lives of 16.11-53.30 h in aqueous buffer solutions (pH 1.3 and 7.4) and 1.63-2.73 min in human plasma, respectively. The title compounds were evaluated in vivo for anti-inflammatory activity in carrageenan induced rat paw oedema model in rats at the doses 45, 90, 150 mg/kg b.w. The test compounds exhibited good anti-inflammatory activity (46.6-53.2 % at the dose of 150 mg/kg b. w.) with respect to niflumic acid (78.7 % at the dose of 90 mg/kg b.w.). The compounds were also screened for in vivo ulcerogenicity, it was observed that the prodrug 5b was significantly less irritating to gastric mucosa than compound 5a and the parent drug niflumic acid 4 following single and chronic oral administration in rats.

Prodrugs of NSAIDs: A Review

“…The prodrug is prepared with novel morpholinoalkyl ester prodrugs (Fig. 61 ) of niflumic acid by esterification of appropriate morpholinylalkyl alcohols [ 52 ]. The ester prodrugs were quantitatively hydrolyzed to the parent drug niflumic acid by enzymatic and/or chemical means.…”

Modeling population pharmacokinetics of morniflumate in healthy Korean men: extending pharmacometrics analysis to niflumic acid, its major active metabolite

“…This was because the bioequivalence data used in this study included only plasma morni umate concentrations following morni umate exposure (i.e., the concentrations of morni umate and ni umic acid could not be quanti ed simultaneously for each individual). Moreover, there is a lack of su cient data on genetic factors related to carboxyl esterase (Talath and Gadad, 2006), which is involved in the metabolism of morni umate to ni umic acid. Therefore, a pharmacokinetic-pharmacodynamic model simulation of ni umic acid was conducted using mean plasma concentration data of morni umate and ni umic acid upon exposure to morni umate (Civelli et al, 1991, Cho et al, 2013).…”

“…Morni umate is a nonsteroidal anti-in ammatory drug (NSAID) with the chemical structure 2-(morpholin-4yl)ethyl 2-{[3-(tri uoromethyl)phenyl]amino}nicotinate (Meher et al, 2022). Upon administration, morni umate undergoes hydrolysis by esterase enzymes in the body, which convert this drug into its pharmacologically active form (ni umic acid) by removing a morpholinoethyl ester group from its structure (Schiantarelli et al, 1984, Talath andGadad, 2006). As a prodrug of ni umic acid, morni umate offers several therapeutic advantages, particularly as a gastroprotective agent that reduces the direct ulcerative side effects of ni umic acid (Schiantarelli et al, 1984).…”